Ebru Karpuzoglu
Steven D. Holladay
Robert M. Gogal Jr- Department of Biomedical Sciences, College of Veterinary Medicine, University of Georgia, Athens, GA, United States
Inflammaging, defined as chronic, low-grade, systemic inflammation that increases with age in the absence of overt infection, is a phenomenon that was first described in 2000 as a member of a growing number of age-related processes that had pleiotropic effects on immune function and disease susceptibility. Although many pathological consequences have been attributed to inflammaging, it remains distinct from immunosenescence and not completely understood. A resurgence of interest in inflammaging has been spurred by recent work demonstrating roles for senescent cells in driving chronic inflammatory signaling and defining the cellular and molecular triggers that sustain cytokine production during aging. Alongside elevations in pro-inflammatory mediators (e.g., IL-6, TNF-α, IL-1β), attention to anti-inflammatory mediators (e.g., IL-10, IL-1Ra) and composite ratios (e.g., IL-6:IL-10) can better index inflammatory balance in older adults. In this review, we summarize the characterization of inflammaging mechanisms, highlight roles for chronic inflammation that are clearly defined in immune system remodeling, and outline questions regarding inflammaging functions in sex differences, hormonal regulation, autoimmunity, and skin biology that still require further exploration.
1 Inflammaging vs. immunosenescence
Inflammaging, first defined in 2000 by Franceschi and colleagues, refers to chronic, low-grade, systemic inflammation that increases with age, even in the absence of overt infection or disease (1). It is characterized by elevated pro-inflammatory cytokines (e.g., IL-6, TNF-α, IL-1β), chemokines, acute-phase proteins, and accumulation of senescent cells with a pro-inflammatory senescence-associated secretory phenotype known as SASP (2–5). Inflammaging is recognized as a force driving age-related diseases, including cardiovascular, neurodegenerative, metabolic, and autoimmune disorders (1, 4).
Immunosenescence describes a functional decline of the immune system affecting both innate and adaptive arms (5–7). Hallmarks include thymic involution, reduced naïve T and B cell output, memory and senescent lymphocyte expansion, impaired antigen presentation, and dysregulated cytokine production (4, 6, 7). Immunosenescence increases susceptibility to infections and reduces vaccine responsiveness, while inflammaging contributes to tissue damage and age-related pathology (3, 5–7). Although immunosenescence and inflammaging are distinct phenomena, they are mechanistically interconnected as senescent immune cells promote inflammaging through the SASP, while chronic inflammation accelerates immune exhaustion and dysfunction (3, 5–7).
2 Triggers of inflammaging
Inflammaging arises from intrinsic aging processes and extrinsic environmental factors converging on molecular pathways and understanding these triggers is essential for identifying intervention points in age-related diseases.
2.1 Internal (aging-related) factors
Senescent cells accumulate with age due to repeated cellular stress, telomere attrition, DNA damage, and oncogenic signaling that can trigger inflammaging, These cells adopt a distinct phenotype with permanent cell cycle arrest and SASP with pro-inflammatory cytokines (IL-6, IL-1β, TNF-α), chemokines, growth factors, proteases driving local and systemic inflammation Coppé et al. showed that oncogene-induced senescent cells secrete IL-6 and IL-8, while Acosta et al. demonstrated that IL-1 signaling reinforces the senescent growth arrest (8, 9). SASP reinforces senescence in an autocrine manner and induces paracrine-driven inflammation to neighboring cells and throughout the organism, contributing to tissue dysfunction, immune evasion, and tumor promotion.
Key SASP molecular regulators include NF-κB, C/EBPβ, and mTOR signaling, which integrate stress signals and drive inflammatory mediator transcription. SASP is modulated by persistent DNA damage responses, dysfunctional mitochondria, and altered chromatin structure, including Lamin B1 loss and senescence-associated heterochromatin foci formation (10–12).
SASP-secreting senescent cells accumulation is implicated in pathogenesis of multiple age-related diseases, including osteoarthritis, atherosclerosis, neurodegeneration, and cancer and are under investigation to improve health span.
2.1.1 Mitochondrial dysfunction and DAMP generation
Mitochondria are central hubs of cellular metabolism and innate immune signaling. With age, mitochondrial dysfunction becomes pervasive involving impaired oxidative phosphorylation, increased reactive oxygen species (ROS) production, and mitochondrial damage-associated molecular patterns (mtDAMPs) release, like mitochondrial DNA (mtDNA) and cardiolipin (13, 14). Damaged mitochondria release mtDNA and ROS acting as DAMPs activating innate immune sensors like NLRP3 inflammasome (12, 15, 16).
Mitochondrial ROS and mtDAMPs-activated NLRP3 inflammasome is a multiprotein complex that catalyzes maturation of pro-inflammatory cytokines IL-1β and IL-18 via caspase-1 activation (17, 18). Impaired mitophagy amplifies this process leading to dysfunctional mitochondria accumulation and a feedforward inflammation loop. Mitochondrial dysfunction intersects with the cGAS-STING and NF-κB pathways amplifying inflammatory responses, where cGAS-STING detects cytoplasmic DNA and activated nuclear NF-κB stimulates proinflammatory cytokine production, contributing to cardiovascular, neurodegenerative, metabolic, and malignant diseases and making mitochondrial health promising targets for inflammaging intervention (18).
2.1.2 Accumulation of damaged macromolecules and other self-debris particles
Aging is associated with progressive accumulation of damaged proteins, lipids, nucleic acids, and cellular debris with declining proteostasis and autophagy. Inefficient apoptotic cell and cellular debris clearance fuel chronic innate immunity activation. Hanayama et al. demonstrated that defective clearance of apoptotic cells leads to chronic inflammation in mouse models (19). These endogenous molecules act as DAMPs activating pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and NOD-like receptors (NLRs) on innate immune cells perpetuating inflammaging. Zhang et al. showed that mitochondrial DAMPs activate neutrophils through TLR9, while Iyer et al. demonstrated that necrotic cells release alarmins that trigger inflammation (14, 20). Persistent PRRs activation by self-DAMPs can result in chronic NF-κB signaling, increased cytokine production, and impaired inflammation resolution.
2.1.3 Gut microbiota dysbiosis and increased intestinal permeability
Gut microbiota undergoes compositional changes with age often shifting toward a pro-inflammatory profile and losing beneficial commensals (21, 22). These age-related changes can increase gut permeability and systemic exposure to microbial PAMPs perpetuating inflammation (23–25). This dysbiosis impairs intestinal barrier integrity, increasing permeability (“leaky gut”) and allowing microbial product translocation such as lipopolysaccharides (LPS) into the circulation (24, 25). LPS and other microbial products activate TLRs, upregulating systemic cytokines (e.g., TNF-α, IL-6, IL-1β) and promoting a chronic pro-inflammatory state characteristic of inflammaging (24–26). Dysbiosis also affects immune cell function, reducing myeloid cells’ ability to clear senescent or apoptotic cells, further exacerbating inflammation. Therapeutic interventions targeting the microbiome (e.g., prebiotics, probiotics, fecal microbiota transplantation) are currently being explored to counteract this inflammatory profile.
2.1.4 Oral microbiota and inflammaging
The oral microbiota have been shown to undergo changes with aging that could contribute to inflammaging. Age-related shifts in oral microbial composition, including increased prevalence of periodontal pathogens such as Porphyromonas gingivalis have been observed in older adults (65–80 years) correlating with elevated serum IL-6 and CRP compared to younger adults (27). Experimental gingivitis in healthy older adults induces systemic endotoxemia with plasma endotoxin increasing from 50 to 201 pg/mL and corresponding rises in soluble CD14 (28). Treatment of periodontitis reduces inflammatory markers in serum CRP and IL-6 after 2 months (29).
2.1.5 Complement and coagulation system chronic activation
Complement system is a major contributor to both inflammation and thrombosis. With age, complement activation dysregulation leads to increased generation of small protein fragment anaphylatoxins, primarily C3a, C4a, and C5a, which bind to their receptors on immune and endothelial cells, promoting cytokine release, leukocyte recruitment, and increased endothelial permeability (30). In healthy individuals aged 70–85 years, plasma C3a levels were significantly elevated (mean 142 ng/mL) compared to young adults aged 20-35 (mean 67 ng/mL), and C3a levels correlated with IL-6 and TNF-α (31).
Terminal complement complexes (C5b-9) can also activate platelets and endothelial cells, fostering a prothrombotic state. Increased coagulation activity and defective complement regulation then amplify these inflammatory cascades (30, 32).
Similarly, coagulation pathways are linked to inflammation. Inflammaging is associated with increased coagulation activity and impaired fibrinolysis, which, in turn, amplify inflammatory signaling through protease-activated receptors (PARs) and tissue factor expression (33). Complement and coagulation dysregulation may then contribute to the pathogenesis of age-related vascular diseases, including atherosclerosis, thrombosis, and heart failure.
2.2 Environmental and lifestyle factors in inflammaging
Environmental and lifestyle factors such as diet, pollution, stress, and chronic infections play a pivotal role in inflammaging by persistently activating immune and inflammatory pathways.
2.2.1 Diet and glycation end products
Dietary patterns rich in saturated fats and sugars accelerate inflammaging by promoting advanced glycation end-products (AGEs) formation. AGEs bind to the receptor for AGEs (RAGE) on immune and endothelial cells, triggering NF-κB-mediated pro-inflammatory cytokine transcription (34). Studies demonstrate that high-AGE diets rich in high-fat, high-sugar increase circulating TNF-α, C-reactive protein, and vascular adhesion molecules, while AGE restriction reduces these markers (24, 34). Visceral adiposity is a potent source of pro-inflammatory cytokines and chemokines, with increased infiltration of immune cells and senescent macrophages in adipose tissue (35, 36). Therefore, dietary modification to reduce AGE intake and the volume of adiposity may help systemic inflammaging attenuation lowering the risk of age-related diseases.
2.2.2 Obesity and sedentarism
Obesity represents a major driver of inflammaging through adipose tissue dysfunction. And visceral adiposity that can secrete pro-inflammatory adipokines including IL-6, TNF-α, and leptin, while reducing anti-inflammatory adiponectin (37, 38). Obese individuals showed increased macrophage infiltration in adipose tissue, with a shift from anti-inflammatory M2 to pro-inflammatory M1 phenotype (39). Sedentary lifestyle was associated with higher levels of leptin and TNF-α, and lower adiponectin-to-leptin ratios, independent of moderate-to-vigorous physical activity levels, suggesting a direct link between sedentary behavior and a pro-inflammatory profile (40).
2.2.3 Environmental pollution
Environmental pollutant exposure has been shown to increase oxidative stress and systemic inflammation due to industrialized lifestyles and varies significantly across global populations (41). Air pollutants including particulate matter (PM), nitrogen oxides, and volatile organic compounds may contribute to oxidative stress induction and mitochondrial dysfunction via activating NF-κB and MAPK pathways in immune and epithelial cells (42, 43). Pollutants can activate aryl hydrocarbon receptor (AhR) promoting Th17-mediated inflammation and suppressing regulatory T cell (Treg) function exacerbating autoimmunity and chronic inflammation (43, 44). Pollutants can also induce epigenetic modifications, including altered DNA methylation and histone modifications, which further dysregulate immune responses and contribute to premature aging (43, 45). Chronic exposure to pollution is associated with a heightened incidence of cardiovascular, respiratory, metabolic, and autoimmune diseases in the older adults, positioning this factor as an environmental inflammaging driver.
2.2.4 Psychological stress
Chronic psychological stress has been shown to be a potent activator of the inflammasome and pro-inflammatory cytokine cascades that elevates systemic cytokine levels. Iwata et al. demonstrated that psychological stress activates the NLRP3 inflammasome through ATP release and P2X7 receptor activation, leading to IL-1β production (46). Frank et al. showed that stress-induced glucocorticoid resistance results in sustained elevation of IL-6 and TNF-α (47). These stress-induced mechanisms may collectively accelerate inflammaging in young adults and are linked to a higher risk of depression, cardiovascular disease, and metabolic syndrome in older adults. Table 1 provides an overview of key triggers and pathways in inflammaging, including internal factors and external factors.
Table 1. Key triggers and pathways in inflammaging.
3 Impact of inflammaging on innate immunity
Aging profoundly alters innate immunity function, phenotype, and molecular signaling of key cellular players. Inflammaging is both a driver and a consequence of these changes with homeostatic shift in innate responses and thus, the predisposition of older individuals to infection, chronic disease, and impaired tissue repair (4, 7, 48).
3.1 Macrophages: central effectors and molecular pathways
Macrophages are central to innate immune response orchestration and are critically involved in inflammation initiation and resolution. In inflammaging, macrophages undergo functional reprogramming, characterized by a low-level activation state and an altered polarization profile (4, 49–51). Aging impairs macrophage polarization, often skewing toward a pro-inflammatory phenotype with increased basal secretion of IL-1β, TNF-α, IL-6, CXCL9 and CXCL10, even in the absence of overt stimulation (52, 53). Zhang et al. demonstrated increased basal IL-1β and TNF-α secretion in aged macrophages, while Becker et al. showed altered polarization profiles (52, 53). This is driven in part by mitochondrial dysfunction, notably reduced mitochondrial calcium (mCa2+) uptake, which amplifies cytosolic calcium signaling and activates the NF-κB pathway, rendering macrophages hyper-responsive to inflammatory stimuli and prone to chronic inflammatory output (54, 55).
The NLRP3 inflammasome is also upregulated with age, primed by NF-κB and activated by mitochondrial ROS, potassium efflux, and lysosomal destabilization, leading to caspase-1-dependent maturation, IL-1β and IL-18 secretion and pyroptotic cell death (pro-inflammatory programmed cell death) (50, 56–58). These processes are further compounded by impaired mitophagy, resulting in dysfunctional mitochondria accumulation and sustained inflammasome activation (54, 58).
Macrophage polarization is influenced by the JAK-STAT3 axis, which regulates pro-inflammatory (M1) and anti-inflammatory (M2) phenotype balance (59, 60). In aging, dysregulated JAK-STAT3 signaling shifts phenotype and pro- and anti-inflammatory outputs, contributing to tissue fibrosis and impaired inflammation resolution (49, 61). Another aged macrophage hallmark is reduced engulfing and clearance of apoptotic cells (efferocytosis) and tissue repair, leading to the accumulation of such apoptotic cells and DAMPs increasing chronic inflammation (50, 62). Aging macrophages respond to and propagate SASP, creating a feed-forward inflammation loop (49, 63) resulting in transition from acute, self-limited inflammation to persistent state, characteristic of inflammaging.
3.2 Neutrophils: altered function and NETosis
Neutrophils also undergo profound changes with age with altered trafficking, impaired phagocytosis, and increased pro-inflammatory mediator release (64, 65). While neutrophil counts may increase with aging, their functional capacity declines, with defects in chemotaxis, phagocytosis, and microbial killing (66). Sapey et al. demonstrated impaired neutrophil chemotaxis with aging, while Wenisch et al. showed reduced phagocytic capacity (64, 66). Inflammaging is associated with an increased propensity for NETosis, the release of web-like neutrophil extracellular traps (NETs), driven by heightened inflammatory signaling and activation of enzymes such as PAD4 (12). However, senescent neutrophils exhibit reduced capacity to release NETs, instability in NET structure, and decreased DNase activity, leading to impaired pathogen clearance and increased risk of tissue damage and fibrosis (12, 67). This could create a biphasic pattern in aging where NETosis is amplified in early phase by chronic inflammation but diminished later by neutrophil senescence leading to ineffective pathogen clearance and tissue damage risk.
3.3 Dendritic cells: impaired tolerance and antigen presentation
Dendritic cells (DCs), essential for bridging innate and adaptive immunity through antigen presentation and cytokine production, display a pro-inflammatory phenotype during aging with increased IL-6 and TNF-α levels but reduced anti-inflammatory cytokines and type I interferons secretion (68, 69). This reduces their antigen presentation capacity, affecting T cell priming and tolerance maintenance contributing to chronic inflammation and self-tolerance breakdown. These changes are linked to epigenetic reprogramming and altered PRR signaling, further exacerbating age-associated immune dysfunction (69, 70).
3.4 Systemic and clinical implications
A cumulative effect of age-related immune alterations is a state in which innate immune cells remain persistently activated, continuously releasing inflammation-promoting molecules even without infection, but showing a reduced ability to respond effectively to new or acute challenges (4, 55, 68).This paradox of chronic activation coupled with varying levels of functional paralysis underlies the increased susceptibility to infections, poor vaccine responses, and heightened risk of chronic inflammatory diseases observed in older adults (4, 7, 51, 55, 68). These could modulate individual susceptibility to inflammaging and related immune diseases (51). Table 2 provides an overview of innate immune changes and underlying molecular pathways in inflammaging.
Table 2. Key innate immune changes in inflammaging and molecular pathways.
In summary, inflammaging fundamentally reprograms innate immunity through a convergence of mitochondrial, transcriptional, and epigenetic mechanisms. These changes render innate immune cells both hyper-inflammatory and functionally compromised, fueling chronic inflammation and immune dysfunction cycle that characterizes age-related diseases (4, 49, 50, 68).
4 Inflammaging impact on adaptive immunity
Aging and chronic inflammatory environment of inflammaging can remodel adaptive immune system, affecting both T and B lymphocyte compartments through changes in cellular composition, function, metabolic programming, and epigenetic regulation. These alterations reshape immune surveillance, cytokine production, tolerance and autoreactivity balance, with far-reaching consequences for immune homeostasis.
4.1 T cell phenotypic remodeling and functional shifts
A defining feature of adaptive immune aging is a diminished naïve T cell pool, a consequence of thymic involution and reduced thymopoiesis, leading to a reduced T cell receptor (TCR) repertoire diversity and a memory and effector phenotype shift (4, 6, 71–75). This is especially pronounced in CD8+ T cells, which show greater naïve cell loss and terminally differentiated, senescent, exhausted subset accumulation. Senescent T cells, particularly within the CD8 compartment, lose key components of their TCR signaling machinery but acquire natural killer (NK)-like properties, including expression of NK cell receptors and cytotoxic mediators such as granzyme B and perforin (4, 74). These cells are not merely dysfunctional but can also be activated in an antigen-independent manner by cytokines, contributing to the pro-inflammatory milieu of inflammaging.
Senescent (CD28−, KLRG1+) and exhausted T cell expansion reduces cytotoxicity and impairs pathogen/tumor clearance (76–81). This T cell exhaustion driven by inflammaging can cause increased susceptibility to infections, reduced vaccine efficacy, higher autoimmunity risk, and chronic inflammatory diseases. T cell differentiation and subset dysregulation in aging shows complex, context-dependent changes. Studies showed that aging impairs T cells’ ability to mount new Th1 responses to pathogens in older adults with reduced capacity to produce Th1 cytokines (IL-2, IFN-γ) when challenged with novel antigens or vaccines (82, 83). However, studies in older adults (mean age 85 years) show preservation or even increase in basal pro-inflammatory Th1 and Th17 cytokine levels, while anti-inflammatory Th2 cytokines (IL-4, IL-10) decline (5, 84, 85). These findings suggest that immunosenescence may reduce responses to new antigens, while inflammaging may contribute to elevated baseline inflammatory cytokines. This could explain why aging T cells appear to produce more inflammatory mediators at rest but respond poorly when challenged with new pathogens.
Aged T cell functions are further shaped by metabolic and epigenetic reprogramming. Naïve T cells rely on mitochondrial oxidative phosphorylation to maintain quiescence, but upon activation, they switch to glycolysis and upregulate nutrient uptake via mTOR pathway (79, 86). During aging, T cells exhibit impaired mitochondrial function, increased ROS production, and altered mTOR signaling, which skews differentiation toward short-lived effector phenotypes and limits memory formation (79, 86). Epigenetically, aged T cells display increased chromatin accessibility at effector loci (e.g., BATF, T-bet) and decreased accessibility at genes involved in quiescence and self-renewal, such as TCF1 and LEF1 (72, 73). These changes are reinforced by DNA methylation and histone modifications, driving quiescence loss and a bias toward effector and exhausted states.
T cell cytokine production is also altered in aging and inflammaging. While some studies report a decline in IFN-γ production by T cells in older men, others show stable or even increased IFN-γ, particularly in older women and in the context of chronic inflammation or immune disease (75, 87–89). The Th1/Th2/Th17 balance is perturbed, with a relative preservation or increase in Th17 and Th1 cytokines (IL-17, IFN-γ, TNF-α), and a reduction in anti-inflammatory cytokines such as IL-4 and IL-10 (71, 88–90). Studies show age-related increases in pro-inflammatory serum IL-6 levels from approximately 1.5 pg/mL in young adults (<30 years) to 2.0 pg/mL in middle-aged (30–60 years) to 3.5 pg/mL in older adults (>60 years), with strong positive correlation (r=0.664, p<0.001) (91). Similarly, TNF-α rises from approximately 1.5 pg/mL in young to 1.8 pg/mL in middle-aged to 1.9 pg/mL in older adults (r=0.368, p=0.003), and IL-1β increases from 0.5 pg/mL to 2.0 pg/mL to 2.3 pg/mL across the same age groups (r=0.281, p=0.027) (91). Notably, IL-17 shows an opposite trend, decreasing significantly with age from approximately 11 pg/mL in young adults to 3 pg/mL in middle-aged to 2 pg/mL in older adults (r=-0.427, p=0.005), while IL-23 remains relatively stable across age groups (91). Anti-inflammatory IL-10 increases with age, though the magnitude is modest (91). The Th17/Treg balance could show age-dependent changes: basal CD4+IL23R+ (Th17) cells continuously increase with age, while the Th17/Treg ratio increases at rest in older individuals but paradoxically decreases after stimulation, accompanied by elevated Foxp3 mRNA and IL-10 protein expression (92).
This shift with age promotes chronic inflammation and tissue damage. Regulatory T cells (Tregs) increase in frequency with age but often display impaired suppressive function and altered cytokine profiles, sometimes acquiring pro-inflammatory characteristics (71, 73, 74, 88).
T cell exhaustion, characterized by sustained expression of inhibitory receptors (PD-1, CTLA-4, KLRG1) and loss of effector function, is a hallmark of chronic antigenic and inflammatory stimulation in aging (4, 74, 90, 93). Exhausted T cells accumulate in tissues and peripheral blood contributing to impaired pathogen and tumor clearance, but also to chronic inflammatory state maintenance. The central exhaustion program regulator TOX transcription factor enforces epigenetic and transcriptional changes locking T cells in this state (74, 93).
4.2 B cell subset dynamics and autoreactivity
B cell development and function are also markedly altered with age. There is a decline in early B cell progenitors, impaired lineage commitment, and reduced output of naïve B cells from bone marrow, driven by intrinsic epigenetic changes and increased protein turnover of key transcription factors such as E2A (E47) (75, 94, 95). Mature B cells show reduced turnover, impaired class-switch recombination, somatic hypermutation, diminished antibody diversity and affinity (94–96). These defects are compounded by altered BCR signaling, increased metabolic activity (glucose uptake, OXPHOS, FAO), and persistent antigenic stimulation.
A key feature of B cell aging is age-associated B cell (ABCs) expansion, a subset characterized by T-bet and CD11c expression, pro-inflammatory cytokine production (IL-6, TNF-α), and propensity for autoreactivity (75, 89, 94, 96). Age-associated B cells (ABCs, DN B cells) and other memory B cell subset expansions can polarize T helper cells toward inflammatory phenotypes (Th1, Th17) via antigen presentation, autoantibodies and pro-inflammatory cytokine secretion, amplifying inflammatory circuit of inflammaging (75, 89, 94, 97, 98). B regulatory cells (Bregs), which normally suppress inflammation through IL-10, IL-35, and TGF-β, may be reduced or functionally impaired in the older adults, further favoring inflammation (94). B subsets and cytokine environment alterations can reduce high-affinity, protective antibody generation and impair memory B cell and plasma cell function (97, 98).
Autoantibody production increases with age, reflecting both a breakdown in central and peripheral tolerance and pro-inflammatory environment of inflammaging (71, 96, 99). Elevated TNF-α from aged B cells is negatively correlated with activation-induced cytidine deaminase (AID) expression, hindering class-switch recombination and somatic hypermutation, but promoting autoreactive clone survival and expansion (96, 99). The IgG autoantibodies from older individuals often display altered glycosylation and sialylation, which can modulate their pro- or anti-inflammatory effects via Fc receptor binding (99). This accumulation of autoantibodies and immune complexes, B cell subsets and B cell-derived cytokines could result in inflammatory feedback amplifying local, systemic inflammation as well as inflammaging contributing to age-related tissue damage and autoimmunity (71, 96, 99, 100).
4.3 T and B cell crosstalk and immune network remodeling
The interplay between B cells and T cells is increasingly recognized as a driver of adaptive immune aging. B cells can promote T cell immunosenescence through direct cell-cell contact, cytokine secretion such as IFN-γ, TNF-α, and TGF-β, and antigen presentation that skews T cell differentiation toward pathogenic effector and exhausted subsets (75, 89, 94). Conversely, T cell-derived cytokines influence B cell activation, differentiation, and antibody production, establishing a feed-forward loop that sustains chronic inflammation and immune dysfunction (75, 89, 94).
Collective T and B cell alterations with aging suggest inflammaging can be characterized by shifts toward pro-inflammatory phenotypes, sustained IFN-γ and Th17 cytokines, exhausted and senescent lymphocyte accumulation, and increased autoreactive antibody production, underpinned by metabolic and epigenetic remodeling. Table 3 provides an overview of age-associated changes in adaptive immune cells, and Table 4 summarizes T and B cell cytokine production changes with inflammaging.
Table 3. Age-associated changes in adaptive immune cells and molecular pathways.
Table 4. Cytokine production by T and B cell subsets in inflammaging.
5 Gender differences, estrogen and inflammaging
Women exhibit stronger adaptive immune responses and higher autoimmune prevalence than do men, while men show greater monocyte activation and systemic inflammaging (101, 102). Immune cells express estrogen and androgen receptors, through which sex hormones modulate TLR signaling, type I IFN responses, and cytokine production, contributing to observed gender differences (101).
Human studies demonstrate sex differences in immune aging, though findings are not universally consistent. While studies suggest men generally exhibit a more pro-inflammatory “inflammaged” profile with aging and women maintain stronger adaptive immunity into later life, this narrative is not without contradictions.
Studies profiled blood immune cells from individuals 22–93 years old and found that after age 65, men exhibited higher innate and pro-inflammatory activity and lower adaptive (T- and B-cell) activity than women (103).Immune aging changes accelerated earlier in men, beginning at ages 62-64, while comparable changes in women occur from 66–71 years onward (93).
Similarly, Huang et al. showed that men aged 60–80 had higher inflammatory monocytes, increased innate signaling, and steeper naïve T cell decline compared to women, who retained greater adaptive immune function into older age (104). Studies noted that females generally display stronger and longer-lasting adaptive immune responses across adulthood and into old age (105). These women also experienced gradual and slower immune decline, while males demonstrated earlier and more marked reduction in T- and B-cell immunity and increased inflammation-driven disease risk. Giefing-Kröll et al. highlighted that men exhibit stronger and earlier decrease in adaptive immune cells with increased innate activity as they age, whereas women maintain adaptive responses longer, with greater immune decline occurring after menopause (106). However, it is important to note that the heterogeneity in findings could reflect differences in study populations, measurement techniques, and environmental factors.
Aged women, especially post-menopause, show rising inflammation with increased C-reactive protein, TNF-α, IL-6, ceruloplasmin, complement C3, fibrinogen, and β2-microglobulin, though this occurs later than in men (107, 108). In animal studies, similar sexual dimorphism was observed. Females tend to mount stronger innate and adaptive responses than males and this difference is generally observed regardless of age. This can become more pronounced after sexual maturity and with aging as shown in female mice generating higher antibody responses to pathogens, while male mice accumulate more inflammatory monocytes with age (109, 110).
Men’s immune cells decline 5–6 years earlier than women’s (111). These differences could stem from hormonal and genetic factors as women have two X chromosomes enriched for immune genes and estrogen, whereas men have higher levels of androgens. Bernardi et al. study (112) reported in healthy adults aged 22–45 years, men had median cytokine levels of IL-1β around 45 pg/ml versus 5 pg/mL in women, IL-6 around 42 pg/mL versus 15 pg/mL in women, and TNF-α about 90 pg/mL in men versus 25 pg/mL in women. However, these data showed extreme variability with ranges extending to very high levels (>500 pg/mL for IL-1β, >300 pg/mL for IL-6), suggesting potential subclinical or lifestyle conditions that may contribute more than sex differences alone.
Men over 65 years exhibited higher IL-6 levels and related markers than age-matched women, correlating with reduced longevity (113). In this study, men aged 51–60 years had IL-6 levels of 0.95 mg/dL versus 0.88 mg/dL in women, and TNF-α of 2.50 mg/dL versus 2.45 mg/dL. In the 61-70-year group, IL-6 levels were 0.88 mg/dL in men and 0.92 mg/dL in women, while TNF-α levels were 2.45 mg/dL and 2.40 mg/dL, respectively.
The most robust circulating biomarkers of inflammaging such as IL-1β, IL-6, TNF-α, and CRP are consistently associated with age-related disease risk with levels modulated by both sex and hormonal status (4, 101, 114). Studies demonstrate that healthy adult men generally have higher circulating IL-1β, IL-6, and TNF-α than women, a difference only partially explained by sex hormones (4, 101, 114).
Females have longer telomeres and higher telomerase activity than males, a difference established at birth and maintained throughout life, largely due to estrogen’s protective effects on telomere maintenance and protection from oxidative stress (101, 115). Leukocyte telomere length, an established biomarker of inflammaging, reflects this sexual dimorphism and may contribute to the delayed onset of age-related diseases observed in women compared to men (115).
Overall data show males accumulate more age-related inflammatory changes (innate cells, cytokines) with decreased adaptive function earlier, whereas pre-menopausal women maintain robust adaptive immunity (T/B cell responses) that can delay inflammaging (103, 110). These gender/sex differences are shaped not only by hormones (i.e. estrogen) but also by genetic and epigenetic factors, including X-linked immune gene mosaicism, microRNA expression and telomerase activity (101, 103, 104, 110). Environmental and lifestyle factors, such as exposure to pollutants, diet, and stress, can further accelerate inflammaging in a sex-dependent manner, with men generally more susceptible to pollutant-induced inflammation and women more affected by indoor pollutants and endocrine disruptors (116).
5.1 Estrogen and cellular senescence in the context of inflammaging
Cellular senescence plays a pivotal role in the development of inflammaging by contributing to the accumulation of senescent cells and pro-inflammatory SASP secretion. Many senescence inducers act through DNA damage and DNA damage response (DDR) pathways, investigating sex differences in these molecular mechanisms has revealed important distinctions that may underlie differential inflammaging patterns between males and females.
Several studies demonstrated estrogen can exert protective effects against genotoxic stress and senescence-related pathways. Estrogen reduces oxidative stress by suppressing mitochondrial ROS release through both direct mitochondrial interaction and activation of mitochondrial estrogen receptors, as shown in skeletal muscle cells, primary neurons, and cerebral endothelial cells (117–119) Estrogen can prevent DNA fragmentation by hydrogen peroxide and etoposide in mouse skeletal muscle cells (120) and promote telomerase expression and activity in human leukocytes, vascular smooth muscle cells, endothelial progenitor cells, as well as in postmenopausal arterial tissue, supporting telomere maintenance to delay cellular senescence (121, 122).
At the level of checkpoint control, estrogen has been shown to inhibit key DDR regulators. In human ER-positive breast cancer cells, estrogen suppresses Chk1, γH2AX, and ATR expression and activity, which downregulates p21, a central senescence effector (123). Inhibition of ER-α in both normal and malignant mammary epithelial cells leads to increased SA-β-gal staining and dephosphorylated RB family proteins, indicating senescence induction (124). Estrogen can upregulate WRN expression in human breast cells, a DNA helicase involved in genome stability and senescence prevention (125).
The absence of estrogen, as seen in postmenopausal women or ovariectomized (OVX) animals, is associated with accelerated senescence and heightened age-related inflammation. In postmenopausal individuals, blood-derived macrophages exhibit reduced markers of anti-inflammatory (M2) activity (126). In OVX mice, bone marrow mesenchymal stem cells display increased p53 and p21 expression, SASP secretion, JAK/STAT pathway activation and decreased IFN-γ expression from splenic lymphocytes (127, 128). Combined administration of IL-7 and IL-15 in OVX female mice induces antigen-independent production of IL-17A and TNF-α by bone marrow memory T cells, reflecting possible chronic low-grade inflammation state (129). These estrogen-deficiency–driven immune alterations not only accelerate tissue aging but also contribute to the persistent inflammatory milieu characteristic of inflammaging.
Estrogen replacement can reverse several of these deleterious effects. In postmenopausal women and OVX mice, estrogen administration downregulates p53 and p21 expression, SASP output, and JAK/STAT signaling (127). Estrogen also reduces SASP markers including GDF-15, IFN-γ, MCP-1, TNF-α, and matrix metalloproteinases (MMP-2, MMP-9) in both whole blood and isolated platelets (130, 131).
However, estrogen can activate signaling cascades that intersect with SASP-promoting pathways, including p38 MAPK, PI3K, and mTOR, particularly in aged tissues (132). This complexity underscores the dualistic nature of estrogen signaling while estrogen generally delays cellular senescence onset and suppresses SASP under physiological conditions, it may promote pro-senescent or inflammatory outcomes under specific pathological conditions.
These findings establish that estrogen exerts context-dependent effects on cellular senescence and inflammaging, providing protection during premenopausal years through contributions to genomic stability, mitochondrial function, and inflammatory control, but transitioning to accelerated senescence and increased inflammatory burden following estrogen deficiency at menopause.
5.2 Inflammaging: is there a difference between young and menopausal women vs men
Multiple studies report postmenopausal women have higher IL-6 levels, an inflammaging marker, and other pro-inflammatory markers than younger premenopausal peers. Healthy nonobese women aged 22–63 years showed increasing serum IL-6 with age, with postmenopausal women having IL-6 levels of 5.2 pg/mL versus 2.6 pg/mL in premenopausal women, higher TNF-α (8.1 vs. 6.7 pg/mL), and slightly lower IL-1β (0.73 vs. 0.81 pg/mL) (133). Notably, estrogen deprivation after menopause enhanced IL-6 levels from PBMC. Higher IL-6 has been reported in postmenopausal women (4.4 pg/mL) compared to reproductive-age women (2.1 pg/mL), while TNF-α decreased after menopause (2.1 pg/mL postmenopausal vs. 3.4 pg/mL reproductive) (134).
Comparing women to men across age groups reveals additional complexity. In women aged 51–60 years (10 of 11 were menopausal), IL-6 averaged 0.88 mg/dL compared to 0.95 mg/dL in men, while in the 61–70 years group, women had 0.92 mg/dL and men 0.88 mg/dL (114). For TNF-α in the 51–60 age range, women had 2.45 mg/dL and men 2.50 mg/dL; in 61–70 years, women had 2.40 mg/dL and men 2.45 mg/dL (114). Sex-related differences in pro-inflammatory cytokine levels are most evident for IL-6 in the 51-60-year age range, where men exhibit notably higher concentrations than women, but the gap narrows and reverses by 61–70 years (114).
Young women in their 20s-40s demonstrate more robust adaptive immunity and lower baseline inflammatory markers compared to age-matched men. Men exhibit significantly higher levels of IL-6 (42 vs. 15 pg/mL), IL-1β (45 vs. 5 pg/mL), and TNF-α (90 vs. 25 pg/mL) than women (112). IL-6 increases with age primarily in men, conferring a longevity disadvantage (135). Both IL-6 and CRP, key biomarkers of inflammaging, remain lower in healthy premenopausal women than age-matched men, possibly due to estrogen’s modulation of cytokine production. Young women also show stronger immune reactivity, including higher antibody titers and more vigorous T-cell responses to pathogens and vaccines than men (105, 109, 136).
Thus, menopause could induce a pro-inflammatory transition, as estrogen loss leads to higher IL-6 and TNF-α output, partly explaining increased chronic disease incidence after menopause. Young women clear infections more efficiently with greater susceptibility to autoimmune and inflammatory conditions, while men’s higher baseline inflammatory cytokine levels established early in adulthood could set the stage for accelerated inflammatory aging compared to premenopausal women.
5.3 Environmental and lifestyle influences on inflammaging by sex differences
Environmental and lifestyle factors interact with sex to shape inflammaging, though additional data are still needed. Unhealthy lifestyle (obesity, poor diet, smoking, chronic stress) amplifies inflammaging in both sexes, but some effects are sex-specific. Obesity represents a major inflammatory source via fat tissue production of IL-6 and TNF-α. Diet-induced obesity models show that male rodents develop higher systemic inflammation than females (137). Obese males have greater pro-inflammatory responses such as higher M1 macrophages in adipose tissue and 2–3 fold higher TNF-α and IL-6 levels than females on high fat diet, while obese females expressed more anti-inflammatory M2 macrophages (138).
Stress and sleep patterns also differ by sex and affect immunity. Chronic psychosocial stress may elevate pro-inflammatory cytokines more in men, though findings are mixed (139). Environmental toxins and pollutants also have sex-differential effects. Men historically have higher exposures to industrial chemicals and smoking, while women have greater exposure to household/outdoor pollutants and endocrine disruptors, which can have an impact on inflammatory responses (140). Diet composition and microbiome interact with sex hormones to alter immune responses (141). Mediterranean-type diets may benefit both sexes, but men tend to accumulate more visceral fat leading to inflammatory environment than women for the same diet/caloric load (142). Men with risk factors (obesity, sedentary life, smoking) often show higher IL-6/CRP levels than comparably affected women (143), while higher CRP concentrations in premenopausal women appear to result from their greater accumulation of subcutaneous fat compared to men (144). Women, by contrast, may manifest environmental stress as different disease risks (e.g. autoimmunity, bone loss) but without as high basal inflammation (145). In summary, lifestyle factors can influence inflammaging differently by sex, though both sexes can suffer inflammaging from poor lifestyle and external factors.
6 Inflammaging in female autoimmunity
Female-predominant autoimmune diseases, including systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, and Hashimoto’s thyroiditis, arise from complex interactions of genetic, epigenetic, hormonal, and environmental factors (109, 146).
Inflammaging is now recognized as a critical background process that amplifies susceptibility to and progression of autoimmunity in women (101, 109, 136). Unlike the episodic chronic inflammation seen in active autoimmune disease, inflammaging involves elevated circulating pro-inflammatory cytokines (IL-6, IL-1β, TNF-α, IFN-γ, CRP), accumulation of senescent immune cells with SASP, altered redox and metabolic states (12, 145).
At the molecular level, inflammaging in female autoimmunity involves persistent NF-κB and JAK-STAT pathway activation, chronic stimulation of PARs such as TLR7, which is X-linked and more expressed in females, expansion of late-differentiated effector T cells and age-associated B cells (ABCs) (12, 147, 148).The ABCs that are more prevalent in aging women secrete high er IL-6, TNF-α, and autoantibody levels, perpetuating SASP and amplifying tissue damage (101, 147). These findings may be suggestive for the overlap between inflammaging and autoimmunity (12), and understanding inflammaging, sex hormones, and autoimmunity intersection is key for intervening therapies.
7 Inflammaging mirroring out: skin implications
The skin provides a unique window into inflammaging processes, serving as both sentinel and contributor to systemic inflammation. Sexual dimorphism extends to skin immunity, with androgens and estrogens differentially affecting skin immune responses (149). Inflammaging in skin is driven by senescent cell accumulation, chronic pro-inflammatory mediator production, extracellular matrix disruption, and skin-resident immune system dysregulation. These processes are amplified by age-related skin microbiome changes that contribute to skin aging phenotypes, impaired barrier function, and increased disease susceptibility.
Senescent dermal fibroblasts accumulate with age and after repeated exposure to UV radiation and oxidative damage, secreting SASP rich in pro-inflammatory cytokines including IL-6, IL-8, TNF-α, and matrix metalloproteinases (MMPs). These SASP factors amplify local inflammation, degrade collagen, and disrupt extracellular matrix (ECM) homeostasis, resulting in dermal thinning, elasticity loss, wrinkles and impaired wound healing (150–152). SASP activates JNK and AP-1 signaling, further upregulating MMPs and accelerating collagen breakdown (150, 151). Chronic inflammation with persistent SASP signaling creates a microenvironment conducive to carcinogenesis and other age-related skin pathologies (151, 152).
Keratinocytes also undergo senescence with age and repeated UV exposure secreting pro-inflammatory cytokines and inducing fibroblast senescence via IL-1 signaling. This establishes paracrine feedback loop that perpetuates tissue inflammation and ECM degradation (150–152). Loss of IGF-1 expression in senescent fibroblasts further impairs keratinocyte survival and differentiation, exacerbating epidermal atrophy and barrier dysfunction (153). Inflammaging can impact on collagen dynamics, pigmentation changes and further impairing epidermal renewal. Senescent fibroblasts display reduced collagen gene expression (COL1A1, COL3A1, COL4A1) and increased MMPs secretion, leading to decreased collagen deposition, increased collagen fragmentation, and weakened ECM (150, 154). This not only results in signs of aging but also impairs wound healing and structural resilience (155, 156).
Skin-resident immune cells are reshaped by inflammaging. Langerhans cells, specialized tissue-resident macrophages with dendritic cell-like antigen-presenting functions, decline in numbers and function with age, impairing immune surveillance and contributing to increased susceptibility to infections and inflammatory dermatoses (150, 153). Skin-resident T cells show age-related compartmental heterogeneity, with the Koguchi-Yoshioka et al. study demonstrating increased CD8+ T cell infiltration and reduced CD4 to CD8 ratio in aged epidermis (157), while Zuelgaray et al. found increased CD4 to CD8 ratio in whole skin explant cultures containing both epidermis and dermis (158), suggesting different skin layers could exhibit distinct T cell distributions that collectively contribute to local inflammation with cytokines entering systemic circulation to promote systemic inflammaging (150, 156).
Inflammaging and skin microbiome dysregulation can interact bidirectionally. With age, protective commensal species in microbiome such as Cutibacterium decline, while pro-inflammatory taxa such as Corynebacterium and Streptococcus expand (159, 160). This dysbiosis alters skin surface pH, lipid composition, and barrier function, creating permissive environment for chronic, low-grade inflammation accelerating collagen degradation and impairing wound healing (159, 160). Age-related microbiome shifts potentially undermine regulatory T cell and antimicrobial peptide protective mechanisms (156, 161).
In addition to these intrinsic factors, environmental and lifestyle factors including UV exposure, pollution, poor sleep and diet accelerate skin inflammaging by promoting oxidative stress, DNA damage, skin barrier and microbiome disruption (150). The cumulative impact is premature skin aging characterized by wrinkles, dryness, impaired barrier function, and a heightened risk of irritation and neoplasia.
8 Conclusion
Our understanding of inflammaging mechanism and responses is rapidly developing. This chronic, low-grade, systemic inflammatory state links aging to immune dysfunction, tissue degeneration, and increased disease susceptibility. Inflammaging is mechanistically distinct from but intimately connected to immunosenescence, driven by intrinsic cellular senescence and extrinsic environmental factors. The interplay between innate and adaptive immune alterations, sex hormones particularly estrogen, and genetic and epigenetic regulators shapes inflammaging’s trajectory and tissue-specific manifestations including skin aging. Cellular senescence, SASP production, immune cell reprogramming, and microbiome shifts converge to amplify these processes, creating systemic repercussions that extend beyond individual organs. Thus, even in our early understanding of inflammaging’s complexity, the pathways that drive it remain intriguing targets for therapeutic intervention.
Author contributions
EK: Conceptualization, Data curation, Methodology, Writing – original draft. RG: Funding acquisition, Supervision, Writing – review & editing. SH: Supervision, Visualization, Writing – review & editing.
Funding
The author(s) declared that financial support was not received for this work and/or its publication.
Conflict of interest
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References
1. Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, et al. Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci. (2000) 908:244–54. doi: 10.1111/j.1749-6632.2000.tb06651.x
2. Aranda JF, Ramirez CM, and Mittelbrunn M. Inflammaging, a targetable pathway for preventing cardiovascular diseases. Cardiovasc Res. (2024) 121:1537–50. doi: 10.1093/cvr/cvae240
3. Franceschi C, Garagnani P, Parini P, Giuliani C, and Santoro A. Inflammaging: A new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol. (2018) 14:576–90. doi: 10.1038/s41574-018-0059-4
4. Fulop T, Larbi A, Pawelec G, Khalil A, Cohen AA, Hirokawa K, et al. Immunology of aging: the birth of inflammaging. Clin Rev Allergy Immunol. (2023) 64:109–22. doi: 10.1007/s12016-021-08899-6
5. Xia S, Zhang X, Zheng S, Khanabdali R, Kalionis B, Wu J, et al. An update on inflamm-aging: mechanisms, prevention, and treatment. J Immunol Res. (2016) 2016:8426874. doi: 10.1155/2016/8426874
6. Wrona MV, Ghosh R, Coll K, Chun C, and Yousefzadeh MJ. The 3 I’s of immunity and aging: immunosenescence, inflammaging, and immune resilience. Front Aging. (2024) 5:1490302. doi: 10.3389/fragi.2024.1490302
7. Liu Z, Liang Q, Ren Y, Guo C, Ge X, Wang L, et al. Immunosenescence: molecular mechanisms and diseases. Signal Transduction Targeted Ther. (2023) 8:200. doi: 10.1038/s41392-023-01451-2
8. Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic ras and the P53 tumor suppressor. PloS Biol. (2008) 6:2853–68. doi: 10.1371/journal.pbio.0060301
9. Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol. (2013) 15:978–90. doi: 10.1038/ncb2784
10. Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP, Raza SR, et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol. (2009) 11:973–9. doi: 10.1038/ncb1909
11. Freund A, Laberge RM, Demaria M, and Campisi J. Lamin B1 loss is a senescence-associated biomarker. Mol Biol Cell. (2012) 23:2066–75. doi: 10.1091/mbc.E11-10-0884
12. Li X, Li C, Zhang W, Wang Y, Qian P, and Huang H. Inflammation and aging: signaling pathways and intervention therapies. Signal Transduct Target Ther. (2023) 8:239. doi: 10.1038/s41392-023-01502-8
13. West AP, Brodsky IE, Rahner C, Woo DK, Erdjument-Bromage H, Tempst P, et al. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature. (2011) 472:476–80. doi: 10.1038/nature09973
14. Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, et al. Circulating mitochondrial damps cause inflammatory responses to injury. Nature. (2010) 464:104–7. doi: 10.1038/nature08780
15. Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol. (2011) 12:222–30. doi: 10.1038/ni.1980
16. Zhou R, Yazdi AS, Menu P, and Tschopp J. A role for mitochondria in NLRP3 inflammasome activation. Nature. (2011) 469:221–5. doi: 10.1038/nature09663
17. Zong Y, Li H, Liao P, Chen L, Pan Y, Zheng Y, et al. Mitochondrial dysfunction: mechanisms and advances in therapy. Signal Transduct Target Ther. (2024) 9:124. doi: 10.1038/s41392-024-01839-8
18. Walker KA, Basisty N, Wilson DM 3rd, and Ferrucci L. Connecting aging biology and inflammation in the omics era. J Clin Invest. (2022) 132:e158448. doi: 10.1172/JCI158448
19. Hanayama R, Tanaka M, Miyasaka K, Aozasa K, Koike M, Uchiyama Y, et al. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science. (2004) 304:1147–50. doi: 10.1126/science.1094359
20. Iyer SS, Pulskens WP, Sadler JJ, Butter LM, Teske GJ, Ulland TK, et al. Necrotic cells trigger a sterile inflammatory response through the NLRP3 inflammasome. Proc Natl Acad Sci U.S.A. (2009) 106:20388–93. doi: 10.1073/pnas.0908698106
21. Claesson MJ, Jeffery IB, Conde S, Power SE, O’Connor EM, Cusack S, et al. Gut microbiota composition correlates with diet and health in the elderly. Nature. (2012) 488:178–84. doi: 10.1038/nature11319
22. Rampelli S, Candela M, Turroni S, Biagi E, Collino S, Franceschi C, et al. Functional metagenomic profiling of intestinal microbiome in extreme ageing. Aging (Albany NY). (2013) 5:902–12. doi: 10.18632/aging.100623
23. Thevaranjan N, Puchta A, Schulz C, Naidoo A, Szamosi JC, Verschoor CP, et al. Age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction. Cell Host Microbe. (2017) 21:455–66 e4. doi: 10.1016/j.chom.2017.03.002
24. Li J, Lv JL, Cao XY, Zhang HP, Tan YJ, Chu T, et al. Gut microbiota dysbiosis as an inflammaging condition that regulates obesity-related retinopathy and nephropathy. Front Microbiol. (2022) 13:1040846. doi: 10.3389/fmicb.2022.1040846
25. Biragyn A and Ferrucci L. Gut dysbiosis: A potential link between increased cancer risk in ageing and inflammaging. Lancet Oncol. (2018) 19:e295–304. doi: 10.1016/S1470-2045(18)30095-0
26. Ferrucci L and Fabbri E. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol. (2018) 15:505–22. doi: 10.1038/s41569-018-0064-2
27. Ogawa T, Hirose Y, Honda-Ogawa M, Sugimoto M, Sasaki S, Kibi M, et al. Composition of salivary microbiota in elderly subjects. Sci Rep. (2018) 8:414. doi: 10.1038/s41598-017-18677-0
28. Wahaidi VY, Kowolik MJ, Eckert GJ, and Galli DM. Endotoxemia and the host systemic response during experimental gingivitis. J Clin Periodontol. (2011) 38:412–7. doi: 10.1111/j.1600-051X.2011.01710.x
29. D’Aiuto F, Parkar M, Andreou G, Suvan J, Brett PM, Ready D, et al. Periodontitis and systemic inflammation: control of the local infection is associated with a reduction in serum inflammatory markers. J Dent Res. (2004) 83:156–60. doi: 10.1177/154405910408300214
30. Zheng R, Zhang Y, Zhang K, Yuan Y, Jia S, and Liu J. The complement system, aging, and aging-related diseases. Int J Mol Sci. (2022) 23:8689. doi: 10.3390/ijms23158689
31. Gaya da Costa M, Poppelaars F, van Kooten C, Mollnes TE, Tedesco F, Wurzner R, et al. Age and sex-associated changes of complement activity and complement levels in a healthy caucasian population. Front Immunol. (2018) 9:2664. doi: 10.3389/fimmu.2018.02664
32. Qiu W, Chen F, Feng X, Shang J, Luo X, and Chen Y. Potential role of inflammaging mediated by the complement system in enlarged facial pores. J Cosmet Dermatol. (2024) 23:27–32. doi: 10.1111/jocd.15956
33. Chu AJ. Tissue factor, blood coagulation, and beyond: an overview. Int J Inflam. (2011) 2011:367284. doi: 10.4061/2011/367284
34. Vlassara H, Cai W, Crandall J, Goldberg T, Oberstein R, Dardaine V, et al. Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy. Proc Natl Acad Sci U.S.A. (2002) 99:15596–601. doi: 10.1073/pnas.242407999
35. Matacchione G, Perugini J, Di Mercurio E, Sabbatinelli J, Prattichizzo F, Senzacqua M, et al. Senescent macrophages in the human adipose tissue as a source of inflammaging. Geroscience. (2022) 44:1941–60. doi: 10.1007/s11357-022-00536-0
36. Zhang X, Wang Q, Wang Y, Ma C, Zhao Q, Yin H, et al. Interleukin-6 promotes visceral adipose tissue accumulation during aging via inhibiting fat lipolysis. Int Immunopharmacol. (2024) 132:111906. doi: 10.1016/j.intimp.2024.111906
37. Fontana L, Eagon JC, Trujillo ME, Scherer PE, and Klein S. Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes. (2007) 56:1010–3. doi: 10.2337/db06-1656
38. Hotamisligil GS, Shargill NS, and Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science. (1993) 259:87–91. doi: 10.1126/science.7678183
39. Lumeng CN, Bodzin JL, and Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest. (2007) 117:175–84. doi: 10.1172/JCI29881
40. Henson J, Yates T, Edwardson CL, Khunti K, Talbot D, Gray LJ, et al. Sedentary time and markers of chronic low-grade inflammation in a high risk population. PloS One. (2013) 8:e78350. doi: 10.1371/journal.pone.0078350
41. Franck M, Tanner KT, Tennyson RL, Daunizeau C, Ferrucci L, Bandinelli S, et al. Nonuniversality of inflammaging across human populations. Nat Aging. (2025) 5:1471–80. doi: 10.1038/s43587-025-00888-0
42. Gavito-Covarrubias D, Ramirez-Diaz I, Guzman-Linares J, Limon ID, Manuel-Sanchez DM, Molina-Herrera A, et al. Epigenetic mechanisms of particulate matter exposure: air pollution and hazards on human health. Front Genet. (2023) 14:1306600. doi: 10.3389/fgene.2023.1306600
43. Bachmann MC, Bellalta S, Basoalto R, Gomez-Valenzuela F, Jalil Y, Lepez M, et al. The challenge by multiple environmental and biological factors induce inflammation in aging: their role in the promotion of chronic disease. Front Immunol. (2020) 11:570083. doi: 10.3389/fimmu.2020.570083
44. Castaneda AR, Pinkerton KE, Bein KJ, Magana-Mendez A, Yang HT, Ashwood P, et al. Ambient particulate matter activates the aryl hydrocarbon receptor in dendritic cells and enhances Th17 polarization. Toxicol Lett. (2018) 292:85–96. doi: 10.1016/j.toxlet.2018.04.020
45. Jung YS, Aguilera J, Kaushik A, Ha JW, Cansdale S, Yang E, et al. Impact of Air Pollution Exposure on Cytokines and Histone Modification Profiles at Single-Cell Levels during Pregnancy. Sci Adv. (2024) 10:eadp5227. doi: 10.1126/sciadv.adp5227
46. Iwata M, Ota KT, Li XY, Sakaue F, Li N, Dutheil S, et al. Psychological stress activates the inflammasome via release of adenosine triphosphate and stimulation of the purinergic type 2x7 receptor. Biol Psychiatry. (2016) 80:12–22. doi: 10.1016/j.biopsych.2015.11.026
47. Frank MG, Fonken LK, Watkins LR, and Maier SF. Acute stress induces chronic neuroinflammatory, microglial and behavioral priming: A role for potentiated nlrp3 inflammasome activation. Brain Behav Immun. (2020) 89:32–42. doi: 10.1016/j.bbi.2020.05.063
48. Averyanova MV, Vishnyakova P, Victoria VK, Valentiva V, Krechetova L, Elchaninov A, et al. Inflammaging from the perspective of gynecological endocrinology. Starting point. Morphology. (2024) 162:5–15. doi: 10.17816/morph.633989
49. Yarbro JR, Emmons RS, and Pence BD. Macrophage immunometabolism and inflammaging: roles of mitochondrial dysfunction, cellular senescence, cd38, and nad. Immunometabolism. (2020) 2:e200026. doi: 10.20900/immunometab20200026
50. Oishi Y and Manabe I. Macrophages in age-related chronic inflammatory diseases. NPJ Aging Mech Dis. (2016) 2:16018. doi: 10.1038/npjamd.2016.18
51. Frasca D and Blomberg BB. Inflammaging decreases adaptive and innate immune responses in mice and humans. Biogerontology. (2016) 17:7–19. doi: 10.1007/s10522-015-9578-8
52. Zhang B, Bailey WM, Braun KJ, and Gensel JC. Age decreases macrophage IL-10 expression: implications for functional recovery and tissue repair in spinal cord injury. Exp Neurol. (2015) 273:83–91. doi: 10.1016/j.expneurol.2015.08.001
53. Becker L, Nguyen L, Gill J, Kulkarni S, Pasricha PJ, and Habtezion A. Age-dependent shift in macrophage polarisation causes inflammation-mediated degeneration of enteric nervous system. Gut. (2018) 67:827–36. doi: 10.1136/gutjnl-2016-312940
54. Seegren PV, Harper LR, Downs TK, Zhao XY, Viswanathan SB, Stremska ME, et al. Reduced mitochondrial calcium uptake in macrophages is a major driver of inflammaging. Nat Aging. (2023) 3:796–812. doi: 10.1038/s43587-023-00436-8
55. Goldberg EL, Shaw AC, and Montgomery RR. How inflammation blunts innate immunity in aging. Interdiscip Top Gerontol Geriatr. (2020) 43:1–17. doi: 10.1159/000504480
56. Guo ZL, Zhou J, Lin XJ, Yuan Q, Dong YL, Liu QB, et al. Regulation of the AGEs-induced inflammatory response in human periodontal ligament cells via the AMPK/NF-kappab/NLRP3 signaling pathway. Exp Cell Res. (2024) 437:113999. doi: 10.1016/j.yexcr.2024.113999
57. Youm YH, Grant RW, McCabe LR, Albarado DC, Nguyen KY, Ravussin A, et al. Canonical NLRP3 inflammasome links systemic low-grade inflammation to functional decline in aging. Cell Metab. (2013) 18:519–32. doi: 10.1016/j.cmet.2013.09.010
58. Sebastian-Valverde M and Pasinetti GM. The NLRP3 inflammasome as a critical actor in the inflammaging process. Cells. (2020) 9:1552. doi: 10.3390/cells9061552
59. Mills CD, Kincaid K, Alt JM, Heilman MJ, and Hill AM. M-1/M-2 macrophages and the th1/th2 paradigm. J Immunol. (2000) 164:6166–73. doi: 10.4049/jimmunol.164.12.6166
60. Peng Y, Zhou M, Yang H, Qu R, Qiu Y, Hao J, et al. Regulatory mechanism of M1/M2 macrophage polarization in the development of autoimmune diseases. Mediators Inflammation. (2023) 2023:8821610. doi: 10.1155/2023/8821610
61. Xia T, Zhang M, Lei W, Yang R, Fu S, Fan Z, et al. Advances in the role of STAT3 in macrophage polarization. Front Immunol. (2023) 14:1160719. doi: 10.3389/fimmu.2023.1160719
62. Hu H, Cheng X, Li F, Guan Z, Xu J, Wu D, et al. Defective efferocytosis by aged macrophages promotes sting signaling mediated inflammatory liver injury. Cell Death Discov. (2023) 9:236. doi: 10.1038/s41420-023-01497-9
63. Elder SS and Emmerson E. Senescent cells and macrophages: key players for regeneration? Open Biol. (2020) 10:200309. doi: 10.1098/rsob.200309
64. Sapey E, Greenwood H, Walton G, Mann E, Love A, Aaronson N, et al. Phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence. Blood. (2014) 123:239–48. doi: 10.1182/blood-2013-08-519520
65. Bui TA, Jickling GC, and Winship IR. Neutrophil dynamics and inflammaging in acute ischemic stroke: A transcriptomic review. Front Aging Neurosci. (2022) 14:1041333. doi: 10.3389/fnagi.2022.1041333
66. Wenisch C, Patruta S, Daxbock F, Krause R, and Horl W. Effect of age on human neutrophil function. J Leukoc Biol. (2000) 67:40–5. doi: 10.1002/jlb.67.1.40
67. Sabbatini M, Bona E, Novello G, Migliario M, and Reno F. Aging hampers neutrophil extracellular traps (NETs) efficacy. Aging Clin Exp Res. (2022) 34:2345–53. doi: 10.1007/s40520-022-02201-0
68. Gao H, Nepovimova E, Adam V, Heger Z, Valko M, Wu Q, et al. Age-associated changes in innate and adaptive immunity: role of the gut microbiota. Front Immunol. (2024) 15:1421062. doi: 10.3389/fimmu.2024.1421062
69. Agrawal A, Agrawal S, and Gupta S. Role of dendritic cells in inflammation and loss of tolerance in the elderly. Front Immunol. (2017) 8:896. doi: 10.3389/fimmu.2017.00896
70. Keenan CR and Allan RS. Epigenomic drivers of immune dysfunction in aging. Aging Cell. (2019) 18:e12878. doi: 10.1111/acel.12878
71. Müller L. From aging to long COVID: exploring the convergence of immunosenescence, inflammaging, and autoimmunity. Front Immunol. (2023) 14:1298004. doi: 10.3389/fimmu.2023.1298004
72. Perdaens O and Pesch VV. Molecular mechanisms of immunosenescene and inflammaging: relevance to the immunopathogenesis and treatment of multiple sclerosis. Front Neurol. (2022) 12:811518. doi: 10.3389/fneur.2021.811518
73. Goronzy JJ, Hu B, Kim C, Jadhav RR, and Weyand CM. Epigenetics of T cell aging. J Leukoc Biol. (2018) 104:691–9. doi: 10.1002/JLB.1RI0418-160R
74. Abbas AA and Akbar AN. Induction of T cell senescence by cytokine induced bystander activation. Front Aging. (2021) 2:714239. doi: 10.3389/fragi.2021.714239
75. Khan S, Chakraborty M, Wu F, Chen N, Wang T, Chan YT, et al. B cells promote T cell immunosenescence and mammalian aging parameters. bioRxiv. (2023), 2023.09.12.556363. doi: 10.1101/2023.09.12.556363
76. Xu W and Larbi A. Markers of T cell senescence in humans. Int J Mol Sci. (2017) 18:1742. doi: 10.3390/ijms18081742
77. Thomas R, Wang W, and Su DM. Contributions of age-related thymic involution to immunosenescence and inflammaging. Immun Ageing. (2020) 17:2. doi: 10.1186/s12979-020-0173-8
78. Thomas AL, Godarova A, Wayman JA, Miraldi ER, Hildeman DA, and Chougnet CA. Accumulation of immune-suppressive cd4 + T cells in aging - tempering inflammaging at the expense of immunity. Semin Immunol. (2023) 70:101836. doi: 10.1016/j.smim.2023.101836
79. Bevilacqua A, Ho PC, and Franco F. Metabolic reprogramming in inflammaging and aging in T cells. Life Metab. (2023) 2:load028. doi: 10.1093/lifemeta/load028
80. Kroemer G and Zitvogel L. CD4(+) T cells at the center of inflammaging. Cell Metab. (2020) 32:4–5. doi: 10.1016/j.cmet.2020.04.016
81. Hawkes JE and O’Connell RM. MicroRNAs, T follicular helper cells and inflammaging. Oncotarget. (2015) 6:32295–6. doi: 10.18632/oncotarget.6025
82. Sandmand M, Bruunsgaard H, Kemp K, Andersen-Ranberg K, Pedersen AN, Skinhoj P, et al. Is ageing associated with a shift in the balance between type 1 and type 2 cytokines in humans? Clin Exp Immunol. (2002) 127:107–14. doi: 10.1046/j.1365-2249.2002.01736.x
83. Sakata-Kaneko S, Wakatsuki Y, Matsunaga Y, Usui T, and Kita T. Altered th1/th2 commitment in human CD4+ T cells with ageing. Clin Exp Immunol. (2000) 120:267–73. doi: 10.1046/j.1365-2249.2000.01224.x
84. Alberti S, Cevenini E, Ostan R, Capri M, Salvioli S, Bucci L, et al. Age-dependent modifications of type 1 and type 2 cytokines within virgin and memory CD4+ T cells in humans. Mech Ageing Dev. (2006) 127:560–6. doi: 10.1016/j.mad.2006.01.014
85. Shchukina I, Bohacova P, and Artyomov MN. T cell control of inflammaging. Semin Immunol. (2023) 70:101818. doi: 10.1016/j.smim.2023.101818
86. Slack M, Wang T, and Wang R. T cell metabolic reprogramming and plasticity. Mol Immunol. (2015) 68:507–12. doi: 10.1016/j.molimm.2015.07.036
87. Bhat P, Leggatt G, Waterhouse N, and Frazer IH. Interferon-gamma derived from cytotoxic lymphocytes directly enhances their motility and cytotoxicity. Cell Death Dis. (2017) 8:e2836. doi: 10.1038/cddis.2017.67
88. Goetzl EJ, Huang MC, Kon J, Patel K, Schwartz JB, Fast K, et al. Gender specificity of altered human immune cytokine profiles in aging. FASEB J. (2010) 24:3580–9. doi: 10.1096/fj.10-160911
89. Zeng QH, Wei Y, Lao XM, Chen DP, Huang CX, Lin QY, et al. B cells polarize pathogenic inflammatory T helper subsets through ICOSL-dependent glycolysis. Sci Adv. (2020) 6:eabb6296. doi: 10.1126/sciadv.abb6296
90. Zhao H, Wu L, Yan G, Chen Y, Zhou M, Wu Y, et al. Inflammation and tumor progression: signaling pathways and targeted intervention. Signal Transduct Target Ther. (2021) 6:263. doi: 10.1038/s41392-021-00658-5
91. Alvarez-Rodriguez L, Lopez-Hoyos M, Munoz-Cacho P, and Martinez-Taboada VM. Aging is associated with circulating cytokine dysregulation. Cell Immunol. (2012) 273:124–32. doi: 10.1016/j.cellimm.2012.01.001
92. Schmitt V, Rink L, and Uciechowski P. The Th17/Treg balance is disturbed during aging. Exp Gerontol. (2013) 48:1379–86. doi: 10.1016/j.exger.2013.09.003
93. Gao Z, Feng Y, Xu J, and Liang J. T-cell exhaustion in immune-mediated inflammatory diseases: new implications for immunotherapy. Front Immunol. (2022) 13:977394. doi: 10.3389/fimmu.2022.977394
94. de Mol J, Kuiper J, Tsiantoulas D, and Foks AC. The dynamics of B cell aging in health and disease. Front Immunol. (2021) 12:733566. doi: 10.3389/fimmu.2021.733566
95. Cancro MP, Hao Y, Scholz JL, Riley RL, Frasca D, Dunn-Walters DK, et al. B cells and aging: molecules and mechanisms. Trends Immunol. (2009) 30:313–8. doi: 10.1016/j.it.2009.04.005
96. Valentino TR, Chen N, Makhijani P, Khan S, Winer S, Revelo XS, et al. The role of autoantibodies in bridging obesity, aging, and immunosenescence. Immun Ageing. (2024) 21:85. doi: 10.1186/s12979-024-00489-2
97. Mouat IC, Goldberg E, and Horwitz MS. Age-associated B cells in autoimmune diseases. Cell Mol Life Sci. (2022) 79:402. doi: 10.1007/s00018-022-04433-9
98. Frasca D and Blomberg BB. Aging induces B cell defects and decreased antibody responses to influenza infection and vaccination. Immun Ageing. (2020) 17:37. doi: 10.1186/s12979-020-00210-z
99. Ludwig RJ, Vanhoorelbeke K, Leypoldt F, Kaya Z, Bieber K, McLachlan SM, et al. Mechanisms of autoantibody-induced pathology. Front Immunol. (2017) 8:603. doi: 10.3389/fimmu.2017.00603
100. Teissier T, Boulanger E, and Cox LS. Interconnections between inflammageing and immunosenescence during ageing. Cells. (2022) 11:359. doi: 10.3390/cells11030359
101. Olivieri F, Marchegiani F, Matacchione G, Giuliani A, Ramini D, Fazioli F, et al. Sex/gender-related differences in inflammaging. Mech Ageing Dev. (2023) 211:111792. doi: 10.1016/j.mad.2023.111792
102. Bonafe M, Prattichizzo F, Giuliani A, Storci G, Sabbatinelli J, and Olivieri F. Inflamm-aging: why older men are the most susceptible to SARS-Cov-2 complicated outcomes. Cytokine Growth Factor Rev. (2020) 53:33–7. doi: 10.1016/j.cytogfr.2020.04.005
103. Márquez EJ, Chung CH, Marcheş R, Rossi RJ, Nehar-Belaid D, Eroğlu A, et al. Sexual-dimorphism in human immune system aging. Nat Commun. (2020) 11:751. doi: 10.1038/s41467-020-14396-9
104. Huang Z, Chen B, Liu X, Li H, Xie L, Gao Y, et al. Effects of sex and aging on the immune cell landscape as assessed by single-cell transcriptomic analysis. Proc Natl Acad Sci U.S.A. (2021) 118:e2023216118. doi: 10.1073/pnas.2023216118
105. Klein SL and Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. (2016) 16:626–38. doi: 10.1038/nri.2016.90
106. Giefing-Kroll C, Berger P, Lepperdinger G, and Grubeck-Loebenstein B. How sex and age affect immune responses, susceptibility to infections, and response to vaccination. Aging Cell. (2015) 14:309–21. doi: 10.1111/acel.12326
107. Sinatora RV, Chagas EFB, Mattera FOP, Mellem LJ, Santos A, Pereira LP, et al. Relationship of inflammatory markers and metabolic syndrome in postmenopausal women. Metabolites. (2022) 12:73. doi: 10.3390/metabo12010073
108. Ramirez MF, Honigberg M, Wang D, Parekh JK, Bielawski K, Courchesne P, et al. Protein biomarkers of early menopause and incident cardiovascular disease. J Am Heart Assoc. (2023) 12:e028849. doi: 10.1161/JAHA.122.028849
109. Karpuzoglu E and Zouali M. The multi-faceted influences of estrogen on lymphocytes: toward novel immuno-interventions strategies for autoimmunity management. Clin Rev Allergy Immunol. (2011) 40:16–26. doi: 10.1007/s12016-009-8188-0
110. Hagg S and Jylhava J. Sex differences in biological aging with a focus on human studies. Elife. (2021) 10:e63425. doi: 10.7554/eLife.63425
111. Hirokawa K, Utsuyama M, Hayashi Y, Kitagawa M, Makinodan T, and Fulop T. Slower immune system aging in women versus men in the Japanese population. Immun Ageing. (2013) 10:19. doi: 10.1186/1742-4933-10-19
112. Bernardi S, Toffoli B, Tonon F, Francica M, Campagnolo E, Ferretti T, et al. Sex differences in proatherogenic cytokine levels. Int J Mol Sci. (2020) 21:3861. doi: 10.3390/ijms21113861
113. Bonafe M and Olivieri F. Inflammaging: the lesson of covid-19 pandemic. Mech Ageing Dev. (2022) 205:111685. doi: 10.1016/j.mad.2022.111685
114. Milan-Mattos JC, Anibal FF, Perseguini NM, Minatel V, Rehder-Santos P, Castro CA, et al. Effects of natural aging and gender on pro-inflammatory markers. Braz J Med Biol Res. (2019) 52:e8392. doi: 10.1590/1414-431X20198392
115. Dalgard C, Benetos A, Verhulst S, Labat C, Kark JD, Christensen K, et al. Leukocyte telomere length dynamics in women and men: menopause vs age effects. Int J Epidemiol. (2015) 44:1688–95. doi: 10.1093/ije/dyv165
116. Caldarelli M, Rio P, Marrone A, Giambra V, Gasbarrini A, Gambassi G, et al. Inflammaging: the next challenge-exploring the role of gut microbiota, environmental factors, and sex differences. Biomedicines. (2024) 12:1716. doi: 10.3390/biomedicines12081716
117. Torres MJ, Kew KA, Ryan TE, Pennington ER, Lin CT, Buddo KA, et al. 17beta-estradiol directly lowers mitochondrial membrane microviscosity and improves bioenergetic function in skeletal muscle. Cell Metab. (2018) 27:167–79 e7. doi: 10.1016/j.cmet.2017.10.003
118. Lejri I, Grimm A, and Eckert A. Mitochondria, estrogen and female brain aging. Front Aging Neurosci. (2018) 10:124. doi: 10.3389/fnagi.2018.00124
119. Razmara A, Sunday L, Stirone C, Wang XB, Krause DN, Duckles SP, et al. Mitochondrial effects of estrogen are mediated by estrogen receptor alpha in brain endothelial cells. J Pharmacol Exp Ther. (2008) 325:782–90. doi: 10.1124/jpet.107.134072
120. Vasconsuelo A, Milanesi L, and Boland R. 17beta-estradiol abrogates apoptosis in murine skeletal muscle cells through estrogen receptors: role of the phosphatidylinositol 3-kinase/Akt pathway. J Endocrinol. (2008) 196:385–97. doi: 10.1677/JOE-07-0250
121. Emmerson E and Hardman MJ. The role of estrogen deficiency in skin ageing and wound healing. Biogerontology. (2012) 13:3–20. doi: 10.1007/s10522-011-9322-y
122. Walker AE, Morgan RG, Ives SJ, Cawthon RM, Andtbacka RH, Noyes D, et al. Age-related arterial telomere uncapping and senescence is greater in women compared with men. Exp Gerontol. (2016) 73:65–71. doi: 10.1016/j.exger.2015.11.009
123. Pedram A, Razandi M, Evinger AJ, Lee E, and Levin ER. Estrogen inhibits atr signaling to cell cycle checkpoints and DNA repair. Mol Biol Cell. (2009) 20:3374–89. doi: 10.1091/mbc.e09-01-0085
124. Liu Z, Wang L, Yang J, Bandyopadhyay A, Kaklamani V, Wang S, et al. Estrogen receptor alpha inhibits senescence-like phenotype and facilitates transformation induced by oncogenic ras in human mammary epithelial cells. Oncotarget. (2016) 7:39097–107. doi: 10.18632/oncotarget.9772
125. Lee SJ, Lee SH, Ha NC, and Park BJ. Estrogen prevents senescence through induction of WRN, Werner syndrome protein. Horm Res Paediatr. (2010) 74:33–40. doi: 10.1159/000313366
126. Toniolo A, Fadini GP, Tedesco S, Cappellari R, Vegeto E, Maggi A, et al. Alternative activation of human macrophages is rescued by estrogen treatment in vitro and impaired by menopausal status. J Clin Endocrinol Metab. (2015) 100:E50–8. doi: 10.1210/jc.2014-2751
127. Wu W, Fu J, Gu Y, Wei Y, Ma P, and Wu J. JAK2/STAT3 regulates estrogen-related senescence of bone marrow stem cells. J Endocrinol. (2020) 245:141–53. doi: 10.1530/JOE-19-0518
128. Karpuzoglu-Sahin E, Hissong BD, and Ansar Ahmed S. Interferon-gamma levels are upregulated by 17-beta-estradiol and diethylstilbestrol. J Reprod Immunol. (2001) 52:113–27. doi: 10.1016/s0165-0378(01)00117-6
129. Cline-Smith A, Axelbaum A, Shashkova E, Chakraborty M, Sanford J, Panesar P, et al. Ovariectomy activates chronic low-grade inflammation mediated by memory T cells, which promotes osteoporosis in mice. J Bone Miner Res. (2020) 35:1174–87. doi: 10.1002/jbmr.3966
130. Faubion L, White TA, Peterson BJ, Geske JR, LeBrasseur NK, Schafer MJ, et al. Effect of menopausal hormone therapy on proteins associated with senescence and inflammation. Physiol Rep. (2020) 8:e14535. doi: 10.14814/phy2.14535
131. Miller VM, Lahr BD, Bailey KR, Heit JA, Harman SM, and Jayachandran M. Longitudinal effects of menopausal hormone treatments on platelet characteristics and cell-derived microvesicles. Platelets. (2016) 27:32–42. doi: 10.3109/09537104.2015.1023273
132. Tower J, Pomatto LCD, and Davies KJA. Sex differences in the response to oxidative and proteolytic stress. Redox Biol. (2020) 31:101488. doi: 10.1016/j.redox.2020.101488
133. Kim OY, Chae JS, Paik JK, Seo HS, Jang Y, Cavaillon JM, et al. Effects of aging and menopause on serum interleukin-6 levels and peripheral blood mononuclear cell cytokine production in healthy nonobese women. Age (Dordr). (2012) 34:415–25. doi: 10.1007/s11357-011-9244-2
134. Cioffi M, Esposito K, Vietri MT, Gazzerro P, D’Auria A, Ardovino I, et al. Cytokine pattern in postmenopause. Maturitas. (2002) 41:187–92. doi: 10.1016/s0378-5122(01)00286-9
135. Bonafe M, Olivieri F, Cavallone L, Giovagnetti S, Mayegiani F, Cardelli M, et al. A gender–dependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity. Eur J Immunol. (2001) 31:2357–61. doi: 10.1002/1521-4141(200108)31:8<2357::aid-immu2357>3.0.co;2-x
136. Ahmed SA, Hissong BD, Verthelyi D, Donner K, Becker K, and Karpuzoglu-Sahin E. Gender and risk of autoimmune diseases: possible role of estrogenic compounds. Environ Health Perspect. (1999) 107 Suppl 5:681–6. doi: 10.1289/ehp.99107s5681
137. Maric I, Krieger JP, van der Velden P, Borchers S, Asker M, Vujicic M, et al. Sex and species differences in the development of diet-induced obesity and metabolic disturbances in rodents. Front Nutr. (2022) 9:828522. doi: 10.3389/fnut.2022.828522
138. Braga Tibaes JR, Barreto Silva MI, Wollin B, Vine D, Tsai S, and Richard C. Sex differences in systemic inflammation and immune function in diet-induced obesity rodent models: A systematic review. Obes Rev. (2024) 25:e13665. doi: 10.1111/obr.13665
139. Bekhbat M and Neigh GN. Sex differences in the neuro-immune consequences of stress: focus on depression and anxiety. Brain Behav Immun. (2018) 67:1–12. doi: 10.1016/j.bbi.2017.02.006
140. Biswas A, Harbin S, Irvin E, Johnston H, Begum M, Tiong M, et al. Sex and gender differences in occupational hazard exposures: A scoping review of the recent literature. Curr Environ Health Rep. (2021) 8:267–80. doi: 10.1007/s40572-021-00330-8
141. He S, Li H, Yu Z, Zhang F, Liang S, Liu H, et al. The gut microbiome and sex hormone-related diseases. Front Microbiol. (2021) 12:711137. doi: 10.3389/fmicb.2021.711137
142. Bedard A, Lamarche B, Corneau L, Dodin S, and Lemieux S. Sex differences in the impact of the mediterranean diet on systemic inflammation. Nutr J. (2015) 14:46. doi: 10.1186/s12937-015-0035-y
143. Bergens O, Nilsson A, Papaioannou KG, and Kadi F. Sedentary patterns and systemic inflammation: sex-specific links in older adults. Front Physiol. (2021) 12:625950. doi: 10.3389/fphys.2021.625950
144. Cartier A, Cote M, Lemieux I, Perusse L, Tremblay A, Bouchard C, et al. Sex differences in inflammatory markers: what is the contribution of visceral adiposity? Am J Clin Nutr. (2009) 89:1307–14. doi: 10.3945/ajcn.2008.27030
145. Martinez de Toda I, Gonzalez-Sanchez M, Diaz-Del Cerro E, Valera G, Carracedo J, and Guerra-Perez N. Sex differences in markers of oxidation and inflammation. Implications Ageing. Mech Ageing Dev. (2023) 211:111797. doi: 10.1016/j.mad.2023.111797
146. Dorak MT and Karpuzoglu E. Gender differences in cancer susceptibility: an inadequately addressed issue. Front Genet. (2012) 3:268. doi: 10.3389/fgene.2012.00268
147. Kronzer VL, Bridges SL Jr., and Davis JM 3rd. Why women have more autoimmune diseases than men: an evolutionary perspective. Evol Appl. (2021) 14:629–33. doi: 10.1111/eva.13167
148. Song Y, Li J, and Wu Y. Evolving understanding of autoimmune mechanisms and new therapeutic strategies of autoimmune disorders. Signal Transduct Target Ther. (2024) 9:263. doi: 10.1038/s41392-024-01952-8
149. Chi L, Liu C, Gribonika I, Gschwend J, Corral D, Han SJ, et al. Sexual dimorphism in skin immunity is mediated by an androgen-ILC2-dendritic cell axis. Science. (2024) 384:eadk6200. doi: 10.1126/science.adk6200
150. Lee YI, Choi S, Roh WS, Lee JH, and Kim TG. Cellular senescence and inflammaging in the skin microenvironment. Int J Mol Sci. (2021) 22:3849. doi: 10.3390/ijms22083849
151. Ghosh K and Capell BC. The senescence-associated secretory phenotype: critical effector in skin cancer and aging. J Invest Dermatol. (2016) 136:2133–9. doi: 10.1016/j.jid.2016.06.621
152. Nan L, Guo P, Hui W, Xia F, and Yi C. Recent advances in dermal fibroblast senescence and skin aging: unraveling mechanisms and pioneering therapeutic strategies. Front Pharmacol. (2025) 16:1592596. doi: 10.3389/fphar.2025.1592596
153. Smith P and Carroll B. Senescence in the ageing skin: A new focus on mTORC1 and the lysosome. FEBS J. (2025) 292:960–75. doi: 10.1111/febs.17281
154. Fullard N, Wordsworth J, Welsh C, Maltman V, Bascom C, Tasseff R, et al. Cell senescence-independent changes of human skin fibroblasts with age. Cells. (2024) 13:659. doi: 10.3390/cells13080659
155. Pajak J, Nowicka D, and Szepietowski JC. Inflammaging and immunosenescence as part of skin aging-a narrative review. Int J Mol Sci. (2023) 24:7784. doi: 10.3390/ijms24097784
156. Agrawal R, Hu A, and Bollag WB. The skin and inflamm-aging. Biol (Basel). (2023) 12:1396. doi: 10.3390/biology12111396
157. Koguchi-Yoshioka H, Hoffer E, Cheuk S, Matsumura Y, Vo S, Kjellman P, et al. Skin T cells maintain their diversity and functionality in the elderly. Commun Biol. (2021) 4:13. doi: 10.1038/s42003-020-01551-7
158. Zuelgaray E, Boccara D, Ly Ka So S, Boismal F, Mimoun M, Bagot M, et al. Increased expression of PD1 and CD39 on CD3(+) CD4(+) skin T cells in the elderly. Exp Dermatol. (2019) 28:80–2. doi: 10.1111/exd.13842
159. Myers T, Bouslimani A, Huang S, Hansen ST, Clavaud C, Azouaoui A, et al. A multi-study analysis enables identification of potential microbial features associated with skin aging signs. Front Aging. (2023) 4:1304705. doi: 10.3389/fragi.2023.1304705
160. Ratanapokasatit Y, Laisuan W, Rattananukrom T, Petchlorlian A, Thaipisuttikul I, and Sompornrattanaphan M. How microbiomes affect skin aging: the updated evidence and current perspectives. Life (Basel). (2022) 12:936. doi: 10.3390/life12070936
161. Woo YR and Kim HS. Interaction between the microbiota and the skin barrier in aging skin: A comprehensive review. Front Physiol. (2024) 15:1322205. doi: 10.3389/fphys.2024.1322205
162. Rea IM, Gibson DS, McGilligan V, McNerlan SE, Alexander HD, and Ross OA. Age and age-related diseases: role of inflammation triggers and cytokines. Front Immunol. (2018) 9:586. doi: 10.3389/fimmu.2018.00586
163. Wu YL, Xu J, Rong XY, Wang F, Wang HJ, and Zhao C. Gut microbiota alterations and health status in aging adults: from correlation to causation. Aging Med (Milton). (2021) 4:206–13. doi: 10.1002/agm2.12167
164. Fransen F, van Beek AA, Borghuis T, Aidy SE, Hugenholtz F, van der Gaast-de Jongh C, et al. Aged gut microbiota contributes to systemical inflammaging after transfer to germ-free mice. Front Immunol. (2017) 8:1385. doi: 10.3389/fimmu.2017.01385
165. Gyriki D, Nikolaidis CG, Bezirtzoglou E, Voidarou C, Stavropoulou E, and Tsigalou C. The gut microbiota and aging: interactions, implications, and interventions. Front Aging. (2025) 6:1452917. doi: 10.3389/fragi.2025.1452917
Keywords: inflammaging, immunosenescence, sex differences, estrogen, skin aging, inflammation
Citation: Karpuzoglu E, Holladay SD and Gogal RMF Jr (2025) Inflammaging: triggers, molecular mechanisms, immunological consequences, sex differences, and cutaneous manifestations. Front. Immunol. 16:1704203. doi: 10.3389/fimmu.2025.1704203
Received: 12 September 2025; Accepted: 19 November 2025; Revised: 11 November 2025;
Published: 05 December 2025.
Edited by:
Rizgar A Mageed, Queen Mary University of London, United KingdomReviewed by:
Roel De Maeyer, University of Oxford, United KingdomYanling Liao, New York Medical College, United States
Andre Luis Lacerda Bachi, Universidade Santo Amaro, Brazil
Copyright © 2025 Karpuzoglu, Holladay and Gogal. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Robert M. Gogal Jr, cmdvZ2FsQHVnYS5lZHU=